Design of self-assembling materials for challenging drug formulations and cell-culture devices

用于具有挑战性的药物配方和细胞培养装置的自组装材料的设计

• 批准号: RGPIN-2018-06912
• 负责人: Mateescu, MirceaAlexandru
• 金额: $ 2.04万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748699
• 关键词: Design; self; assembling; materials; challenging

Design of self-assembling materials for challenging drug formulations and cell culture devicesThe conceptual core of the proposed research is that “Minor modifications can generate Major changes” in certain self-assembling polymeric excipient features. Several polyhydroxylic materials may be stabilized by strong interchain hydrogen association and self-assembling processes. Starch is a natural polysaccharide presenting double helix (B type) or single helix (V type) morphological forms that coexist with disordered regions. The V-type helix structures present a moderately hydrophobic inner surface that can hold iodine or even some fatty molecules. Among the current drugs, some of them are very low soluble (i.e. non-steroidal anti-inflammatory drugs, as ibuprofen) and thus difficult to formulate for controlled delivery. Other drugs present a very high solubility (such as the antidiabetic metformin) and are also difficult to formulate for sustained release, causing low efficiency and undesirable side effects due to their liberation at improper sites. A major objective of this research is to conceive new and challenging pharmaceutical forms of drugs which are known as difficult to formulate because of their too low or too high solubility. Our hypothesis is that a proper derivatization could increase the diameter of the inner cavity of starch V-helices that may locate hydrophobic drugs. The Carboxymethyl(CM)-Starch, an anionic derivative charged with CM groups, is expected to present a cavity size larger than that of nonmodified Starch. Consequently CM-Starch can hold larger and more hydrophobic agents. A new ampholytic Starch, the CM-AE-Starch, carrying both anionic (CM) and cationic aminoethyl (AE) groups is proposed as an excipient able to delay the release of drugs with absorption at lower intestine or colon. This ampholytic excipient is seems self-stabilized not only by hydrogen associations, but also by ionic interactions and appears adequate to formulate highly soluble agents (as Metformin). A second main objective is to introduce novel biomaterials for tissue culture, for implants and xenografts (i.e. aorta prosthesis). Polyvinyl alcohol (PVA) polymer have been proven as acceptable biomaterial with interesting mechanical and film-forming characteristics due to its strong self-assembling capacity. However, previous reports showed a low colonisation of PVA devices and that certain implants of PVA generate signs of irritation and formation of fibrosis surrounding tissues. Chitosan, another natural carbohydrate, was suggested to be associated with several biocompatible materials, but it presents a poor solubility and its applications may be limited. Our hypothesis is that chitosan modified as CarboxyEthyl(CE)-Chitosan in association to PVA will generate biomaterials of interest for implants and vascular grafts and for devices for hepatocyte and neurons in culture.

设计具有挑战性的药物配方和细胞培养装置的自组装材料拟议研究的概念核心是，在某些自组装聚合物赋形剂特性中，"微小的修改可以产生重大变化"。几种多羟基材料可以通过强链间氢缔合和自组装过程来稳定。淀粉是一种天然多糖，具有双螺旋（B型）或单螺旋（V型）形态，并伴有无序区。V型螺旋结构呈现出适度疏水的内表面，可以容纳碘甚至一些脂肪分子。在目前的药物中，它们中的一些是非常低可溶性的（即非甾体抗炎药，如布洛芬），因此难以配制用于控制递送。其他药物具有非常高的溶解度（例如抗糖尿病的二甲双胍），并且也难以配制用于持续释放，由于它们在不适当的部位释放而导致低效率和不期望的副作用。这项研究的一个主要目标是构思新的和具有挑战性的药物形式，这些药物由于溶解度太低或太高而难以配制。我们的假设是，适当的衍生化可以增加淀粉V-螺旋的内腔直径，可以定位疏水药物。羧甲基（CM）-淀粉，一种带CM基团的阴离子衍生物，预期呈现比未改性淀粉更大的空腔尺寸。因此，CM-淀粉可以容纳更大和更疏水的试剂。一种新的两性淀粉，CM-AE-淀粉，带有阴离子（CM）和阳离子氨乙基（AE）基团，被提出作为一种赋形剂，能够延迟药物的释放，在较低的肠或结肠吸收。这种两性赋形剂似乎不仅通过氢缔合，而且通过离子相互作用而自稳定，并且似乎足以配制高度可溶的药剂（如二甲双胍）。第二个主要目标是引入用于组织培养、植入物和异种移植物（即主动脉假体）的新型生物材料。聚乙烯醇（PVA）聚合物由于其强大的自组装能力，已被证明是可接受的生物材料，具有有趣的机械和成膜特性。然而，之前的报告显示PVA器械的定植率较低，某些PVA植入物会产生刺激迹象，并在组织周围形成纤维化。壳聚糖是另一种天然碳水化合物，被认为与几种生物相容性材料结合，但其溶解性差，其应用可能受到限制。我们的假设是，改性为羧乙基（CE）-壳聚糖与PVA结合的壳聚糖将产生用于植入物和血管移植物以及用于培养肝细胞和神经元的装置的感兴趣的生物材料。